Mutations that disrupt the dystrophin glycoprotein complex (DGC) cause muscular dystrophy [Durbeej et al., Curr Opin Genet Dev 12: 349-361 (2002); Ervasti, Biochim Biophys Acta 1772: 108-117 (2007); Rahimov et al., J Cell Biol 201: 499-510 (2013)]. Dystrophin and its associated proteins localize to the muscle plasma membrane, acting as a linker between the intracellular cytoskeleton to the extracellular matrix [Ervasti et al., J Cell Biol 122: 809-823 (1993); Cohn et al., Muscle Nerve 23: 1456-1471 (2000)]. Large deletions in the dystrophin gene account for Duchenne muscular dystrophy (DMD), and those mutations that maintain the reading frame of dystrophin cause the milder Becker muscular dystrophy (BMD). This observation has been the basis for developing antisense sequences that will induce additional exon skipping events and restore reading frame. Exon skipping, by design, generates an internally truncated and partially functional protein. Clinical trials that test exon skipping in DMD are advancing [Kinali et al., Lancet Neurol 8: 918-928 (2009); Cirak et al., Lancet 378: 595-605 (2011); van Deutekom et al., The New England Journal of Medicine 357: 2677-2686 (2007); Goemans et al., The New England Journal of Medicine 364: 1513-1522 (2011); Lu et al., Mol Ther Nucleic Acids 3: e152 (2014)].
In heart and muscle, the sarcoglycan subcomplex within the DGC is composed of four single pass transmembrane subunits: α, β, γ, and δ-sarcoglycan [Ervasti et al., Cell 66: 1121-1131 (1991); Ozawa et al., Muscle Nerve 32: 563-576 (2005)]. Loss-of-function mutations in genes encoding α, β, γ, and δ-sarcoglycan cause the Limb Girdle Muscular Dystrophies type 2E, 2F, 2C, 2D, respectively [Roberds et al., Cell 78: 625-633 (1994); Bonnemann et al., Nat Genet 11: 266-273 (1995); Noguchi et al., Science 270: 819-822 (1995); Nigro et al., Nat Genet 14: 195-198 (1996)].